U.S. Pat. No. 5,006,528 to Oshiro et al. discloses 7-[(4-phenylpiperazino)-butoxy] carbostyrils, which include aripiprazole, as dopaminergic neurotransmitter antagonists.
Aripiprazole which has the structure
is an atypical antipsychotic agent useful in treating schizophrenia. It has poor aqueous solubility (<1 μg/mL at room temperature). When formulated as an intramuscular (IM) injectable solution, aripiprazole has been found to cause unacceptable (moderate to severe) tissue irritation at the muscular site with many water-miscible co-solvent systems, and water-immiscible solvent and co-solvent systems such as hexonoic acid: medium chain triglyceride (10:90), polyethylene glycol 400:ethanol:lactic acid (35:15:50), benzyl alcohol:sesame oil (10:90), benzyl alcohol:medium chain triglyceride (10:90), benzyl alcohol:tributyrin (5:95), and polysorbate 80 in 25 mM tartaric acid.
Cyclodextrins are known for their use in increasing solubility of drugs. They function by forming inclusion complexes with hydrophobic molecules. Unfortunately, there are many drugs for which cyclodextrin complexation either is not possible or produces no apparent advantages as disclosed by J. Szejtli, Cyclodextrins in Drug Formulations:Part II, Pharmaceutical Technology, 24–38, August, 1991.
U.S. Pat. Nos. 5,134,127 and 5,376,645 each to Stella et al. disclose sulfoalkyl ether cyclodextrin derivatives and their use as solubilizing agents for water-insoluble drugs for oral, intranasal or parenteral administration including intravenous and intramuscular. Stella et al. disclose an inclusion complex of the water-insoluble drug and the sulfoalkyl ether cyclodextrin derivative and pharmaceutical compositions containing same. Examples of sulfoalkyl ether cyclodextrin derivatives disclosed include mono-sulfobutyl ether of β-cyclodextrin and monosulfopropyl ether of β-cyclodextrin. Examples of water-insoluble drugs are set out in column 7 starting at line 25 and include, among others, benzodiazepines, chlorpromazine, diazepam, mephorbarbital, methbarbital, nitrazepam, and phenobarbital.
U.S. Pat. No. 6,232,304 to Kim et al. discloses inclusion complexes of aryl-heterocyclic salts such as the tartrate salt of ziprasidone in a cyclodextrin such as β-cyclodextrin sulfobutyl ether (SBECD), and hydroxypropyl-β-cyclodextrin (HPBCD), and use of such inclusion complexes in oral and parenteral formulations.
Japanese Patent Application No. 09301867A2 dated Nov. 25, 1997 discloses antidepressant compositions in the form of tablets containing aripiprazole.
EP1145711A1 dated Oct. 17, 2001 (based on U.S. Application Ser. No. 2000-547948 filed Apr. 12, 2000) discloses flash-melt oral dosage formulations containing aripiprazole.
U.S. Pat. No. 5,904,929 to Uekama et al. discloses trans-mucosal and transdermal pharmaceutical compositions containing a drug and a peracylated cyclodextrin as a solubilizing agent. Examples of drugs include antidepressants such as amitriptyline HCl, amoxapine, butriptyline HCl, clomipramine HCl, desipramine HCl, dothiepin HCl, doxepin HCl, fluoxetine, gepirone, imipramine, lithium carbonate, mianserin HCl, milnacipran, nortriptyline HCl and paroxetine HCl; anti-muscarinic agents such as atropine sulphate and hyoscine; sedating agents such as alprazolam, buspirone HCl, chlordiazepoxide HCl, chlorpromazine, clozapine, diazepam, flupenthixol HCl, fluphenazine, flurazepam, lorazepam, mazapertine, olanzapine, oxazepam, pimozide, pipamperone, piracetam, promazine, risperidone, selfotel, seroquel, sulpiride, temazepam, thiothixene, triazolam, trifluperidol and ziprasidone; anti-migraine drugs such as alniditan and sumatriptan; beta-adrenoreptor blocking agents such as atenolol, carvedilol, metoprolol, nebivolol and propranolol; anti-Parkinsonian drugs such as bromocryptine mesylate, levodopa and selegiline HCl; opioid analgesics such as buprenorphine HCl, codeine, dextromoramide and dihydrocodeine; parasympathomimetics such as galanthamine, neostigmine, physostymine, tacrine, donepezil, ENA 713 (exelon) and xanomeline; and vasodilators such as amlodipine, buflomedil, amyl nitrite, diltiazem, dipyridamole, glyceryl trinitrate, isosorbide dinitrate, lidoflazine, molsidomine, nicardipine, nifedipine, oxpentifylline and pentaerythritol tetranitrate.